Small-Molecule Inhibitor of Flaviviral NS3-NS5 Interaction with Broad-Spectrum Activity and Efficacy <i>In Vivo</i>
Marta Celegato, Mattia Sturlese, Vivian Vasconcelos Costa, Marta Trevisan, Angélica Samer Lallo Dias, Ingredy Passos, Celso Martins Queiroz‐Junior, Lorenzo Messa, Annagiulia Favaro, Stefano Moro, Mauro Martins Teixeira, Arianna Loregian, Beatrice Mercorelli
Abstract
More than one-third of the human population is at risk of infection by different mosquito-borne flaviviruses. Despite this, no specific antiviral drug is currently available. In this work, using a computational approach based on molecular dynamics simulation and virtual screening of ~1 million small-molecule structures, we identified a compound that targets the interaction between the two sole flaviviral enzymes, i.e., NS3 and NS5. This compound demonstrated pan-serotype anti-DENV activity and pan-flavivirus potential in infected cells, low propensity to select viral resistant mutant viruses, and efficacy in a mouse model of dengue. Broad-spectrum antivirals are much awaited, and this work represents a significant advance toward the development of therapeutic molecules with extended antiflavivirus potential that act by an innovative mechanism and could be used alone or in combination with other antivirals.